Aralkyl formyl-alkyl piperazine derivatives and their uses as a cerebral nerve protective agent

ABSTRACT

Aralkyl formyl alkyl piperazine derivatives 
                         
Pharmaceutical compositions comprising the same, and methods of using them as a neuroprotective agent. Pharmaceutical results indicate that these compounds have excellent neuroprotective activities and fewer side effects.

FIELD OF INVENTION

This invention relates to aralkyl formylalkyl piperazine derivatives andtheir applications as a neuro-protective agent.

TECHNICAL BACKGROUND

Cerebral accidents (such as stroke), especially ischemic apoplexy, iscurrently the third biggest cause of death. It is also the major factorthat causes long-term loss of living abilities. In developed countries,strokes make up 10% of the death among men and 17% of the death amongwomen. With the aging of population, it is predicted that there will bea rise of 13% in stroke patients during the next 3 years. Three fourthsof stroke survivors will be disabled or dysfunctional, which results inhighly increased medical cost and other serious social problems.

There are now two kinds of therapeutic medicines for the treatment ofischemic apoplexy:

1. Drugs, which induce the ischemia areas to reperfusion, and open upblocked blood vessels, resulting in recovery of cerebral blood flow, andsurvival of ischemic brain tissue. These agents are mainlythrombolytics, anticoagulants, vasodilators, radical cleansers, brainfunction accelerants and thrombolytic compositions of Chinese medicines.

2. Neuroprotective agents, which prevent damage to nerves caused byischemia during the early stage of acute ischemic apoplexy.

The safety and efficiency of the first category of medicines arecontroversial, especially because of individual differences of patients.In particular, some of the drugs may cause unwanted bleeding aggravatingischemia and its symptoms and increasing the early stage mortality rate.Therefore, their clinical use has been limited.

The second category of medicines is neuroprotecting agents. Studies showthat when the brain is in an ischemic state, Excitatory Amino Acid(EAA), a central neurotransmitter, is released in large amounts, acts onEAA receptors, mostly on the effector-comlex (N-methyl-D-aspartatereceptor, NMDA receptor), and then opens the Ca²⁺ and Na²⁺ channels,changes the ion permeability, and causes imbalance of the ions insideand outside of the neural cells. This primarily will result in largein-flow the Ca²⁺ and Na²⁺, which causes swelling and death of nervecells. In theory, if the activity of NMDA receptor is inhibited partly,the in-flow of Ca²⁺ can be reduced greatly, and then the ischemic braininjury induced by NMDA receptor will be effectively prevented.

Recent discoveries of different kinds of EAA receptor antagonists haveenabled a new approach to treating ischemic brain injuries. Among them,NMDA receptor antagonists are the main candidates for developing newdrugs for preventing and treating ischemic apoplexy. Many NMDA receptorantagonists such as GV-150526A, AR-R15896, ACEA-1021, and ZD-9379 arebeing tested in clinical phases.

NMDA receptor competitive antagonists have two acid groups and highpolarity, and are hard to permeate the blood-brain barrier. Their oralbioavailability is low. The piperazine derivative CPP and its analoguesare highly selective, strong receptor antagonists, can permeate theblood-brain barrier and have activity after oral administration (Fritz,K. I., Brain Res. 729(1) 66-74, 1996). Ly-274614 is now one of the mosteffective NMDA receptor competitive antagonists (Cheung, N. S., Eur. J.Pharmacol., 313(1/2), 159-162, 1996). However, the above-mentionedantagonists have low therapeutic index, with side effects such asdamages to motor neuron.

Disjunctive anesthetics acting on cation channel such as PCP and MK-801are all non-competitive antagonists. These non-competitive antagonistscan easily permeate the blood brain barrier; however, they have lowselectivity and serious toxicity. Thus they have no or little clinicalvalue.

Since the 1990s, new compounds have been continuously entering clinicaltrials. It is a long and hard task in this research area to design andsynthesize selective and effective NMDA receptor modulators, and thenovel antagonists with the lowest psychic and mental toxicities. Thistask also has great social and economic values.

DESCRIPTION OF THE INVENTION

The first aspect of the present invention is to provide aralkylformylalkyl piperazine derivatives which have medical value. The aim isto overcome the defects of some present anti-ischemic apoplexy agents,such as induced bleeding, difficulty on transmitting blood brainbarrier, low oral bioavailability, low selectivity and high nervous andbehavioral toxicities.

The second aspect of the present invention is to provide the applicationof the above aralkyl formylalkyl piperazine derivatives asneuroprotective agents, especially in the treatment of ischemic cerebralapoplexy.

The third aspect of the present invention is to supply pharmaceuticalcompositions for the treatment of ischemic cerebral apoplexy.

The aralkyl formylalkyl piperazine derivatives described in presentinvention are free base or salts of the compounds represented by thefollowing general formula:

in which the salts are independently one of hydrochloride, hydrobromide,sulfate, trifluoroacetate or methanesulfonate, and preferablyhydrochloride or hydrobromide. The salt can contain between 0.5-3molecules of hydrate water.

In the above formula,

Ar₁ and Ar₂ independently represent:

each of R₁, R₂, R₃ and R₄ can represent any one of hydrogen, a C₁-C₃alkyl group, a C₅ or C₆ cycloalkyl group, phenyl, substituted phenyl,hydroxyl, methoxy, ethoxy, amino, substituted amino, halogen, carboxylicacid, carboxylic ester, nitryl or acetonitrile grouping;

R₁, R₂ and R₃ represent preferably any one of hydrogen, an alkyl grouphaving C₁-C₃, hydroxyl, amino, substituted amino, carboxylic ester; R₄is preferably hydrogen, hydroxyl, alkoxy, nitryl, halogen, amino,substituted amino or a C₁-C₃ alkyl group;

X represents one of —CHOH—, —CO—, —CONH—, —CH═CH—, O, N, —SO₂— or —SO—;

X is preferably one of —CHOH—, —CO— or —CONH—;

Y represents one of C, N, or O.

Y is preferably C or N.

Z represents a five or six-member ring containing at least one of C, S,N or O; and

n, m₁ and m₂ are independently 0, 1, 2, or 3.

The preferable compounds are included as follows:

Code Chemical Name IV-1 N¹-benzoyl-N⁴-phenacyl-piperazine, IV-2N¹,N⁴-diphenacyl-piperazine, IV-3N¹-(4-nitrobenzoyl)-N⁴-phenacyl-piperazine, IV-4N¹-(2-acetoxy-1-oxo-2-phenylethyl)-N⁴-(1-benzoylethyl) piperazine, IV-5N¹-phenacyl-N⁴-(4-chlorophenacyl) piperazine, IV-6 N¹,N⁴-di(4-chlorophenacyl) piperazine, IV-7N¹-(2-naphthoylmethyl)-N⁴-phenacyl-piperazine, IV-8N¹-(1-benzoylethyl)-N⁴-phenacyl-piperazine, IV-9N¹-phenacyl-N⁴-(4-methoxyphenacyl) piperazine, IV-10 N¹,N⁴-di(1-benzoylethyl) piperazine, IV-11 N¹-phenacyl-N⁴-(4-nitrophenacyl)piperazine, IV-12 N¹-phenylacetyl-N⁴-phenacyl-piperazine, IV-13N¹-(1-benzoylethyl)-N⁴-phenacyl-piperazine, IV-14 N¹,N⁴-di(4-methoxyphenacyl) piperazine, IV-15 N¹-phenacyl-N⁴-[(2-hydroxy)phenylacetyl] piperazine, IV-16 N¹-(4-methoxyphenacyl)-N⁴-[(2-hydroxy)phenylacetyl] piperazine, IV-17N¹-(1-benzoylethyl)-N⁴-[2-hydroxy-2-(4-chlorophenyl)acetyl] piperazine,IV-18 N¹-(1-benzoylethyl)-N⁴-[(2-hydroxy) phenylacetyl] piperazine,IV-19 N¹-phenacyl-N⁴-[2-hydroxy-2-(4-chlorophenyl) acetyl] piperazine,IV-20 N¹-phenacyl-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine, IV-21 N1-[2-(benzylamino)-2-oxo-ethyl]-N⁴-cinnamylpiperazine, IV-22 N¹-phenacyl-N⁴-(2,4-difluorobenzylsulfonyl)piperazine, IV-23 N¹-phenacyl-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazine IV-24 N¹-phenacyl-N⁴-[2-(phenylamino)-2-oxo-ethyl] piperazineIV-25 N¹,N⁴-di[2-(benzylamino)-2-oxo-ethyl] piperazine IV-26N¹-(1-benzoylethyl)-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine IV-27N¹-(4-chlorophenacyl)-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine IV-28N¹-(4-methoxyphenacyl)-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine IV-29N¹-phenacyl-N⁴-[2-(R-1-phenylethanamino)-2-oxo-ethyl] piperazine IV-30N¹-phenacyl-N⁴-[2-(4-methoxybenzylamino)-2-oxo-ethyl] piperazine IV-31N¹-phenacyl-N⁴-[2-(2-pyridylmethylamino)-2-oxo-ethyl] piperazine IV-32N¹-phenacyl-N⁴-[2-(3,4-methylenedioxybenzylamino)-2-oxo-ethyl]piperazine IV-33N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine IV-34 N¹-benzoyl-N⁴-(2-phenylethyl-2-ol) piperazineIV-35 N¹-(4-nitrobenzoyl)-N⁴-(2-phenylethyl-2-ol) piperazine IV-36N¹-phenacyl-N⁴-(2-phenylethyl-2-ol) piperazine IV-37N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(2-phenylethyl-2-ol) piperazineIV-38 N¹-(4-methoxyphenacyl)-N⁴-(3-phenylpropyl-3-ol) piperazine IV-39N¹-(4-chlorophenacyl)-N⁴-(2-phenylethyl-2-ol) piperazine IV-40N¹-(4-methoxyphenacyl)-N⁴-(2-phenylethyl-2-ol) piperazine IV-41N¹-(1-benzoylethyl)-N⁴-(2-phenylethyl-2-ol) piperazine IV-42N¹-[2-(4-acetamidophenyl)-2-oxo-ethyl]-N⁴-(2-phenylethyl-2-ol)piperazine IV-43N¹-(2-hydroxy-1-oxo-2-phenylethyl)-N⁴-(phenylpropane-2-yl-3-ol)piperazine IV-44N¹-(S-2-hydroxy-1-oxo-2-phenylethyl)-N⁴-(1-benzoylethyl) piperazineIV-45 N¹-phenacyl-N⁴-(3-fluorophenylmethylsulfonyl) piperazine IV-46N¹-phenacyl-N⁴-(3-bromophenylmethylsulfonyl) piperazine IV-47N¹-phenacyl-N⁴-(3-iodophenylmethylsulfonyl) piperazine IV-48N¹-phenacyl-N⁴-(3-cyanophenylmethylsulfonyl) piperazine IV-49N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-[2-(1-phenylethanamino)-2-oxo-ethyl] piperazine IV-50 N¹-phenacyl-N⁴-(2-fluorobenzylsulfonyl)piperazine IV-51 N¹-phenacyl-N⁴-(2,5-difluorobenzylsufonyl) piperazineIV-52 N¹-phenacyl-N⁴-(2,5-dichlorobenzylsufonyl) piperazine IV-53N¹-phenacyl-N⁴-(4-phenoxybenzylsulfonyl) piperazine IV-54N¹-phenacyl-N⁴-[2-(benzenesulfonylmethyl)benzylsulfonyl] piperazineIV-55 N¹-phenacyl-N⁴-(4-trifluoromethylbenzylsulfonyl) piperazine IV-56N¹-phenacyl-N⁴-(4-phenylbenzylsulfonyl) piperazine IV-57N¹-phenacyl-N⁴-(3-methoxybenzylsulfonyl) piperazine IV-58N¹-phenacyl-N⁴-[4-(2-cyanophenyl)benzylsulfonyl] piperazine IV-59N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(2,4-difluorobenzylsulfonyl)piperazine IV-60N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(2,5-difluorophenylmethylsulfonyl)piperazine IV-61N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-[4-(2-cyanophenyl)benzylsulfonyl]piperazine IV-62N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-[2-(benzenesulfonylmethyl)benzylsulfonyl] piperazine IV-63N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(3,4-dichlorobenzylsulfonyl)piperazine IV-64N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(4-nitrobenzylsulfonyl) piperazineIV-65N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine IV-66N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-(4-methoxyphenacyl)piperazine IV-67N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-(4-Chlorophenacyl)piperazine IV-68N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-(4-methylsulfonylphenacyl)piperazine IV-69N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine IV-70N¹-(4-chlorophenacyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine

Particularly preferable isN¹-phenacyl-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazine.

Their structures are shown in Table 1.

TABLE 1 The Structure of Compounds Code Ar₁ Ar₂ R₁ R₂ R₃ X m₁ m₂ n IV-1Ph Ph H 0 0 C═O 1 0 0 IV-2 Ph Ph H H 0 C═O 1 0 1 IV-3

Ph 0 H 0 C═O 1 0 0 IV-4 Ph Ph CH₃ 0 OCOCH₃ C═O 0 1 1 IV-5 Ph

H H 0 C═O 1 0 1 IV-6

H H 0 C═O 1 0 1 IV-7

Ph H H 0 C═O 1 0 1 VI-8 Ph Ph CH₃ H 0 C═O 1 0 1 IV-9 Ph

H H 0 C═O 1 0 1 IV-10 Ph Ph CH₃ CH₃ 0 C═O 1 0 1 IV-11 Ph

H H 0 C═O 1 0 1 IV-12 Ph Ph H 0 H C═O 0 1 1 IV-13 Ph Ph H H 0 C═O 1 0 2IV-14

H H 0 C═O 1 0 1 IV-15 Ph Ph H 0 OH C═O 0 1 1 IV-16

Ph H 0 OH C═O 0 1 1 IV-17 Ph

CH₃ 0 OH C═O 0 1 1 IV-18 Ph Ph CH₃ 0 OH C═O 0 1 1 IV-19 Ph

H 0 OH C═O 0 1 1 IV-20 Ph

H CH₃ 0 CO 1 0 1 IV-21

Ph H H 0 CH═CH 1 0 1 IV-22 Ph

H 0 H SO₂ 0 1 1 IV-23 Ph Ph H H H CONH 1 1 1 IV-24 Ph Ph H H 0 CONH 1 01 IV-25

Ph H H H CONH 1 1 1 IV-26 Ph Ph CH₃ H H CONH 1 1 1 IV-27

Ph H H H CONH 1 1 1 IV-28

Ph H H H CONH 1 1 1 IV-29 Ph Ph H H CH₃ CONH 1 1 1 IV-30 Ph

H H H CONH 1 1 IV-31 Ph

H H H CONH 1 1 1 IV-32 Ph

H H H CONH 1 1 1 IV-33

Ph CH₃ H H CONH 1 1 1 IV-34 Ph Ph 0 H 0 CHOH 1 0 0 IV-35

Ph 0 H 0 CHOH 1 0 0 IV-36 Ph Ph H H 0 CHOH 1 0 1 IV-37

Ph H H 0 CHOH 1 0 1 IV-38

Ph H H 0 CHOH 2 0 1 IV-39

Ph H H 0 CHOH 1 0 1 IV-40

Ph H H 0 CHOH 1 0 1 IV-41 Ph Ph CH₃ H 0 CHOH 1 0 1 IV-42

Ph H H 0 CHOH 1 0 1 IV-43

Ph 0 CH₃ 0 CHOH 1 0 0 IV-44

Ph 0 CH₃ 0 C═O 1 0 0 IV-45 Ph

H 0 H —SO₂— 0 1 1 IV-46 Ph

H 0 H —SO₂— 0 1 1 IV-47 Ph

H 0 H —SO₂— 0 1 1 IV-48 Ph

H 0 H —SO₂— 0 1 1 IV-49

Ph CH₃ H CH₃ CHOH 1 1 1 IV-50 Ph

H 0 H —SO₂— 0 1 1 IV-51 Ph

H 0 H —SO₂— 0 1 1 IV-52 Ph

H 0 H —SO₂— 0 1 1 IV-53 Ph

H 0 H —SO₂— 0 1 1 IV-54 Ph

H 0 H —SO₂— 0 1 1 IV-55 PH

H 0 H —SO₂— 0 1 1 IV-56 Ph

H 0 H —SO₂— 0 1 1 IV-57 Ph

H 0 H —SO₂— 0 1 1 IV-58 Ph

H 0 H —SO₂— 0 1 1 IV-59

H 0 H —SO₂— 0 1 1 IV-60

H 0 H —SO₂— 0 1 1 IV-61

H 0 H —SO₂— 1 1 1 IV-62

H 0 H —SO₂— 1 1 1 IV-63

H 0 H —SO₂— 0 1 1 IV-64

H 0 H —SO₂— 0 1 1 IV-65

Ph CH₃ H H CONH 1 1 1 IV-66

CH₃ H 0 CO 1 0 1 IV-67

CH₃ H 0 CO 1 0 1 IV-68

CH₃ H 0 CO 1 0 1 IV-69

H CH₃ 0 CHOH 1 0 1 IV-70

H CH₃ 0 CHOH 1 0 1

The above-mentioned compounds can be prepared by the following twosynthetic routes.

Synthetic route 1:

Synthetic route 2:

Piperazine is used as a starting material to prepare the above-mentionedcompounds. The N atom of the piperazine ring is protected by formylgroup first, and then alkylated, finally the formyl group is removed byalkaline hydrolysis to obtain compound (III) with a higher purity andyield. The total yield of three procedures is about 40%. Compound (III),an important intermediate, is alkylated at N⁴ with corresponding halideto obtain compound (IV). When using K₂CO₃/DMF, the reaction can takeplace at room temperature, and the yield is about 80%. If usingK₂CO₃/CH₃COCH₃, NaHCO₃/C₂H₅OH, or Et₃N/CHCl₃ as reaction systems, thereaction it needs reflux for about 8-24 h, and the color of the reactionmix will deepen as time passes. This will reduce the quality and yieldof the products. Compounds IV-1 to IV-33 and IV-44 to IV-68 are obtainedby the above mentioned procedures.

The goal compounds IV-34 to IV-43, IV-69 and IV-70 contain difunctionalcarbonyl and hydroxyl groups. N-benzyl piperazine is reacted withcorresponding bromo-aralkyl ketones to obtain N₁, N₄-disubstitutedcompound (VI). Compound (VI) is reduced by KBH₄ and then hydrogenated by10% Pd—C at 70° C. in HAC to give compound (VIII). Reduction andhydrogenation of compound (VI) also can be carried out in one stepthrough step h. But when the activity of carbonyl is weak, there arestill many unreduced carbonyl materials left. Therefore, carbonyl groupshould be first reduced by KBH₄ before hydrogenation in order to obtaincompound (VIII) with sufficient purity.

The goal compounds IV-34 to IV-43, IV-69 and IV-70 can be obtained byusing a key intermediate compound (VIII) with halogen-aralkyl ketones.

Halogenated aralkyl formyl alkyl compounds in steps b, d and f can beobtained commercially, but can also be prepared with bromine or copperbromide corresponding aralkyl ketones using methods known in theliterature.

The inventors discovered that aralkyl formyl alkyl piperazinederivatives in the present invention are effective against ischemiccerebral apoplexy, and especially, they have therapeutic activities foracute ischemia cerebral infarction. Also, these compounds haveneuroprotective activities after ischemic cerebral apoplexy. Therefore,the compounds from this invention can be used to develop acutetherapeutic agents against ischemia cerebral infraction and aneuroprotective agent after ischemic cerebral apoplexy.

Using well-known methods in the art an effective amount of the compoundsfrom this invention can be combined with any pharmaceutically acceptablecarriers to prepare clinical solid formulations, such as tablets,powders, capsules or injections, etc.

The carriers mentioned above represent the routine pharmaceuticalcarriers, such as dilutents, excipents (water, etc), filling materials(starch, sugar, etc), adhesives (fibrin derivatives, gelatin, polyvinyl,pyrrolidone, etc), wetting agents (glycerin, etc), surface active agents(cetanol, etc), disintegrants (calcium carbonate, etc) and lubricants(talc powder, calcium stearate, magnesium stearate, etc).

According to claims of this invention, the content of the compound isabout 0.1-99.5% in the tablet, powder, capsule or injection.

The inventive compounds can be taken by the patients in the form of oraladministration, injection and so on. For oral administration, thecompounds can be prepared into regular solid formulations, such astablets, powders or capsules. For injection, they can be prepared intoliquid form.

The dosage of these compounds could be regulated according to the ageand the weight of the patients, and specific cases of diseases. Dailywhole dosage can be 2-50 mg/kg (po) or 1-20 mg/kg (iv).

The compounds in this invention have showed potent prevention andtherapeutic actions on global cerebral ischemia and focal cerebralischemia on animals. Their therapeutic effects are much better thanpreviously known related drugs.

The inventors also discovered that the inventive compounds have lowtoxicity levels and fewer side effects for the central nervous system.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. The curve of IV23 restraining the current induced by 100 μM NMDA

EXAMPLES General Preparation 1 N-aralkyl formyl alkyl piperazinedihydrochloride (III)

A mixture of piperazine (258 g, 3 mol) and methyl formate (180 g, 3 mol)was refluxed for 8 h, the excessive piperazine was removed in vacuo, andcollected at 130-134° C./8-10 mm-Hg 240 g of N-formyl piperazine wasobtained (70%).

A mixture of the above product (310 mmol), aralkyl formylalkyl halogen(372 mmol), K₂CO₃ (465 mmol) and KI (30 mmol) in 320 ml of acetone wasrefluxed for 8-16 h, filtered off; the filtrate was evaporated in vacuo.5% NaOH (350 ml) was added to the residue, after refluxed for 10 h, andthen adjusted to a ph of 8 by 6 N HCl, extracted with CHCl₃ (200 ml×3).The combined organic layer was washed with 50 ml of water and saline,dried (MgSO₄), filtered and evaporated. The residue was dissolved in 20ml of ethanol and then adjusted to a ph of 3 by HCl/C₂H₅OH (5N), theresulting precipitate was recrystallized from aqueous ethanol to obtainN-aralkyl formylalkyl piperazine dihydrochloride (III) (55-60%).

General Preparation 2 N¹-aralkylformylalkyl-N⁴-aralkyl piperazinedihydrochloride (IV)

A mixture of compound (III) (10 mmol), aralkyl halogen(12 mmol), KI(1mmol) and K₂CO₃(35 mmol) in DMF(50 ml) was stirred at 25° C.-60° C. for8-12 h, filtrated, and then evaporated to dryness, 50 ml of water andEtOAc (100 ml×3) were added to the residue, the organic layer was washedwith saline, dried (MgSO₄). Filtered and evaporated, the residue wasdissolved by 30 ml of ethanol and then adjusted to a PH of 2 byHCl/C₂H₅OH (5N); the resulting precipitate was recrystallized fromethanol or CH₃OH to obtain the title product (IV)(60-85%).

General Preparation 3 N¹-benzyl-N⁴-aralkyl formyl alkyl piperazinedihydro chloride (VI)

A mixture of piperazine (350 mmol), KOH (100 mmol) andhexadecyl-trimethyl ammonium bromide (CTAB, 1 mmol) in water (18 ml) washeated to get a solution. Thereafter, benzyl chloride (100 mmol) in 140ml of benzene was added to the solution dropwise at 70° C., and refluxedfor 1 h. The organic layer was washed with water and saline, dried(MgSO₄), filtered and evaporated, the residue was dissolved by 50 ml ofethanol and adjusted to a PH of 2 by HCl/C₂H₅OH (5N), the resultingprecipitate was recrystallized from ethanol to obtain N-benzylpiperazine dihydrochloride (55-86%).

A mixture of N-benzyl piperazine dihydrochloride (20 mmol), aryl formylalkyl halide (24 mmol), K₂CO₃ (7 mmol) and KI (2 mmol) in 100 ml ofacetone was treated according to the general preparation 2 to obtaincompound (VI) (65-75%).

General Preparation 4 N¹-benzyl-N⁴-aralkanol piperazine dihydrochloride(VII)

To a mixture of compound (VI) (3.5 mmol) and KHCO₃ (8.75 mmol) inmethanol (60 ml) was added KBH₄ (14 mmol), stirred at room temperaturefor 2 h, and then at 50° C. for 1 h, adjusted to a PH of 3 by 1N aqueousNaOH and then filtered. The filtrate was extracted with EtOAC (40 ml×3),washed with saline, evaporated to dryness, which was dissolved in 20 mlof ethanol, and adjusted to a PH of 2 by HCl/C₂H₅OH (5N), the resultingprecipitate was recrystallized from ethanol to obtain the title compound(60-80%).

General Preparation 5 N-aralkanol piperazine dihydrochloride (VIII)

To a mixture of the above compound (VII) in HAc (60 ml) was added 10%Pd—C (0.4 g), stirred with H₂ at 70° C. for 4 h, filtered off andevaporated to dryness, which was dissolved in 10 ml of ethanol, andadjusted to a PH of 2 by HCl/C₂H₅OH (5N), the resulting precipitate wasrecrystallized from ethanol to obtain the title compound (80-85%).

Example 1 (IV-2) N¹,N⁴-diphenacyl piperazine dihydrochloride

A mixture of piperazine (2 g, 23.22 mmol), 2-chloro-1-phenylethanone(7.89 g) and K₂CO₃ (8 g, 58.08 mmol) in 30 ml of DMF was stirred at 50°C. for 8 h, and treated according to the general preparation 2 to give6.6 g of compound (IV-2) (72%), mp 258-259° C., M⁺ 322.

Elemental analysis (found): C₂₀H₂₂N₂O₂.2HCl (C, 60.91%; H, 6.40%; N,7.26%). ¹HNMR(DMSO-d₆): δ3.46(m, 8H, piperazine-H), 5.09(s, 4H,2COCH₂N), 7.59-8.02 (m, 10H, ArH).

Example 2 (IV-7) N¹-(2-naphthoylmethyl)-N⁴-phenacyl-piperazinedihydrochloride

A mixture of N-formyl piperazine (20 g, 175 mmol),2-chloro-1-phenylethanone (32.5 g, 210 mmol) and K₂CO₃ (36 g, 262 mmol)in 180 ml of acetone was treated according to the general preparation 1to give N-phenacyl piperazine dihydrochloride, 28 g (57%), mp 246-8° C.(dec).

A mixture of 2-bromo-1-(naphthalen-2-yl)ethanone (0.95 g, 3.8 mmol),N-phenacyl piperazine dihydrochloride (0.89 g, 3.2 mmol) and K₂CO₃ (1.56g, 11.2 mmol) in 30 ml of DMF was stirred at 50° C. for 10 h, andtreated according to the general preparation 2 to give compound (IV-7),0.88 g (60.69%), mp 236-237° C., M⁺ 373.

Elemental analysis (found): C₂₄H₂₄N₂O₂.2HCl.1/2H₂O.(C, 63.41%; H, 5.87%;N, 5.96%). ¹HNMR(DMSO-d₆/D₂O):δ3.56 (m, 8H, piperazine-H), 4.90(s, 2H,PhCOCH₂), 5.03(s, 2H), 7.54-8.63 (m, 12H, ArH).

Example 3 (IV-8) N¹-(1-benzoylethyl)-N⁴-phenacyl-piperazinedihydrochloride

A mixture of 2-bromo-1-phenylpropan-1-one (3 mmol), N-phenacylpiperazine dihydrochloride (2.5 mmol) and K₂CO₃ (8.75 mmol) in 30 ml ofDMF was treated according to the general preparation 2 to give compound(IV-8), 0.64 g (62%), mp 236-238° C., M⁺ 336.

Elemental analysis (found): C₂₁H₂₄N₂O₂.2HCl (C, 62.02%; H, 6.64%; N,6.57%). ¹HNMR(DMSO-d₆):δ1.73(d, J=6.0, 3H, COCH(CH₃)N), 3.56(m, 8H,piperazine-H), 5.44 (m, br, 1H, COCHN), 4.90(s, 2H, PhCOCH₂),7.55-8.05(m, 10H, ArH).

Example 4 (IV-9) N¹-phenacyl-N⁴-(4-methoxyphenacyl)piperazinedihydrochloride

A mixture of 2-chloro-1-(4-methoxyphenyl)ethanone (3 mmol), N-phenacylpiperazine dihydrochloride (3 mmol) and K₂CO₃ (10 mmol) in 30 ml of DMFwas treated according to the general preparation 2 to give compound(IV-9), 0.68 g (62%), mp 226-228° C., M⁺ 352.

Elemental analysis (found): C₂₁H₂₄N₂O₃.2HCl.H₂O (C, 57.13%; H, 6.10%; N,6.23%). ¹HNMR(DMSO-d₆): δ2.05 (s, 3H, CH₃O), 3.56(m, 8H, piperazine-H),5.07-5.12 (m, 4H, COCH₂N), 7.53-8.04(m, 9H, ArH).

Example 5 (IV-10) N¹,N⁴-di(1-benzoylethyl)piperazine dihydrochloride

A mixture of piperazine (1.5 mmol), 2-bromo-1-phenylpropan-1-one (3mmol), and K₂CO₃ (8.75 mmol) in 30 ml of DMF was stirred at 50° C. for 8h, then was treated according to the general preparation 2 to givecompound (IV-10), 0.55 g (85%), mp 240-242° C., M⁺ 350.

Elemental analysis (found): C₂₂H₂₆N₂O₂.2HCl.1/2H₂O (C, 61.40%; H, 6.74%;N, 6.64%). ¹HNMR(DMSO-d₆): δ1.73(d, J=6.0, 6H, 2COCH(CH₃)N), 3.56(m, 8H,piperazine-H), 5.44 (m, br, 2H, COCHN), 7.53-8.06(m, 10H, ArH).

Example 6 (IV-11) N¹-phenacyl-N⁴-(4-nitrophenacyl)piperazinedihydrochloride

A mixture of 2-chloro-1-(4-nitrophenyl)ethanone (3.2 mmol), N-phenacylpiperazine dihydrochloride (3 mmol), and K₂CO₃ (9 mmol) in 30 ml of DMFwas treated according to the general preparation 2 to give compound(IV-11), 0.71 g (61%), mp 204-205° C., M⁺ 367.

Elemental analysis (found): C₂₀H₂₁N₃O₄.2HCl.3/2H₂O (C, 51.71%; H, 5.80%;N, 8.99%). ¹HNMR (DMSO-d₆): δ 3.56(m, 8H, piperazine-H), 5.09-5.21(m,4H, 2COCH₂N), 7.55-9.05 (m, 9H, ArH).

Example 7 (IV-13) N¹-(1-benzoylethyl)-N⁴-phenacyl piperazinedihydrochloride

A mixture of 3-bromo-1-phenylpropan-1-one (1.5 g, 8.9 mmol), N-phenacylpiperazine dihydrochloride (2.05 g, 7.4 mmol) and K₂CO₃ (21.75 mmol) in30 ml of DMF was treated according to the general preparation 2 to givecompound (IV-13), 0.64 g (76%), mp 204-205° C., M⁺ 336.

Elemental analysis (found): C₂₁H₂₄N₂O₂.2HCl (C, 61.17%; H, 6.37%; N,6.48%). ¹HNMR(DMSO-d₆): δ 3.37-3.41 (m, 4H, NCH₂CH₂CO), 3.55 (m, 8H,piperazine-H), 5.15 (s, 2H, COCH₂N), 7.43-7.95 (m, 10H, ArH).

Example 8 (IV-18)N¹-(1-benzoylethyl)-N⁴-[(2-hydroxy)phenylacetyl]piperazine hydrochloride

A mixture of 2-bromo-1-phenylpropan-1-one (3 mmol), N-(2-hydroxy-phenylacetyl)piperazine hydrochloride (2.5 mmol) and K₂CO₃ (8.75 mmol) in 30ml of DMF was treated according to the general preparation 2 to givecompound (IV-18), 0.65 g (67%), M⁺ 353.

Elemental analysis (found): C₂₁H₂₄N₂O₃.HCl (C, 64.80%; H, 6.42%; N,7.20%). ¹HNMR(DMSO-d₆): δ1.73 (d, J=6.0, 3H, COCH(CH₃)N), 3.56 (m, 8H,piperazine-H), 4.77 (s, 1H, PhCHCO), 5.44 (m, br, 1H, COCHN),7.55-8.05(m, 10H, ArH).

Example 9 (IV-20)N¹-phenacyl-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazinedihydrochloride

A mixture of 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one(3.8 mmol), N-phenacyl piperazine dihydrochloride (0.89 g, 3.2 mmol) andK₂CO₃ (1.56 g, 11.2 mmol) in 30 ml of DMF are stirred at 50° C. for 10h, then was treated according to the general preparation 2 to givecompound(IV-19), 1.09 g (61%), M⁺ 451.

Elemental analysis (found): C₂₆H₂₇ClN₂O₃.2HCl.2H₂O. ¹HNMR(DMSO-d₆/D₂O):δ 1.70 (d, J=6.0, 3H, COCH(CH₃)N), 3.56(m, 8H, piperazine-H), 4.90(s,2H, PhCOCH₂), 5.41(m, br, 1H, COCHN), 8.64-9.11(m, 4H, ArH).

Example 10 (IV-21) N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-cinnamylpiperazine dihydrochloride

A mixture of N-benzyl-2-chloroacetamide (3.9 mmol),trans-1-cinnamylpiperazine dihydrochloride (5.1 mmol, prepared by usingthe general preparation 1) and K₂CO₃ (8.5 mmol) in 30 ml of DMF wastreated according to the general preparation 2 to give compound(IV-21),0.75 g (69%), mp 226-228° C., M⁺ 349.

Elemental analysis (found): C₂₂H₂₇N₃O.2HCl.H₂O(C, 59.97% H, 7.02% N,9.65%). ¹HNMR(DMSO-d₆):δ3.46-3.57(m, 10H, piperazine-H), 3.87-3.98 (m,2H, CH═CH), 4.37 (m, 2H, NCH₂CH═CH), 6.24(t, 1H, NHCO), 6.90(t, 2H,PhCH2NH), 7.27-7.48 (m, 10H, ArH). IR (KBr): v3310, 3070, 2380, 1660,1595, 1450, 1280, 1000, 980, 950, 745, 690.

Example 11 (IV-22) N¹-phenacyl-N⁴-(2,4-difluorobenzylsulfonyl)piperazinehydrochloride

A mixture of 2,4-difluorobenzylsulfonylchloride (3.5 mmol), N-phenacylpiperazine dihydrochloride (3 mmol), and K₂CO₃ (10.5 mmol) in 30 ml ofDMF was treated according to the general preparation 2 to give compound(IV-22), 0.81 g (71%), M⁺ 412.

Elemental analysis (found): C₁₉H₂₀F₂N₂O₃S.HCl.3/2H₂O (C, 57.21%; H,5.89%; N, 7.10%). ¹HNMR (DMSO-d₆): δ 3.56 (m, 8H, piperazine-H), 4.89(s,2H, ClSO₂CH₂), 5.09(s, 2H, COCH₂N), 7.24-8.05(m, 8H, ArH).

Example 12 (IV-23) N¹-phenacyl-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazine dihydrochloride

This compound has the formula as defined in claim 1, wherein Ar₁ and Ar₂represent phenyl respectively; R₁, R₂, and R₃, each represents hydrogen;

X represents amido; n=m₁=m₂=1.

A mixture of N-phenacyl piperazine dihydrochloride (1 g, 3.6 mmol),chloroacetyl-benzylamine (0.73 g, 4 mmol, prepared bychloroacetylchloride and benzylamine in 2N aqueous NaOH), KI (10 mg) andK₂CO₃ (1.8 g, 13 mmol) in 30 ml of DMF was stirred at 50° C. for 8 h,then filtered, and evaporated off the solvent, the residue was extractedwith 20 ml of water and EtOAC (50 ml×3). Combined organic layer waswashed with water and saline, dried (MgSO₄), filtered and evaporated.The residue was dissolved by 10 ml of ethanol and then adjusted to a PHof 2 by HCl/C₂H₅OH (5N), the resulting precipitate was recrystallizedfrom aqueous ethanol or methanol to obtain compound (IV-23), 0.84 g(55%), mp208-210° C., M⁺ 351.

Elemental analysis: C₂₁H₂₅N₃O₂.2HCl. Found (wt %): C, 59.40; H, 6.45; N,9.87. Theoretical (wt %): C, 59.55; H, 6.43; N, 9.93. IR (KBr): v 3180,2950, 1690, 1670, 1570 cm⁻¹. ¹HNMR(DMSO-d₆): δ 3.35-3.46 (m, 8H,piperazine-H), 3.89 (s, 2H, PhCH₂), 4.32 (s, 2H, NCH₂CON), 4.88 (s, 2H,COCH₂N), 7.23-7.96 (m, 10H, ArH), 9.13(s, NH).

Purity (HPLC): >99%

Example 13 (IV-26)N¹-(1-benzoylethyl)-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazinedihydro-chloride

A mixture of chloroacetylbenzylamine (3.06 mmol),N-[2-(benzylamino)-2-oxo-ethyl]piperazine dihydrochloride (3 mmol,prepared by using the general preparation 1) and K₂CO₃ (10.5 mmol) in 30ml of DMF was treated according to the general preparation 2 to givecompound (IV-26), 0.91 g (80%), M⁺ 365.

Elemental analysis (found): C₂₂H₂₅N₃.2HCl.H₂O. ¹HNMR(DMSO-d₆): δ1.74(d,J=6.0, 3H, COCH(CH₃)N), 3.56(m, 8H, piperazine-H), 4.14 (s, 2H, PhCH₂),4.35(s, 2H, NCH₂CON), 5.44 (m, br, 1H, COCHN), 7.23-8.03 (m, 10H, ArH)

Example 14 (IV-28)N¹-(4-methoxyphenacyl)-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazinedihydrochloride

A mixture of chloroacetylbenzylamine (3.06 mmol), N-(4-methoxyphenacyl)piperazine dihydrochloride (3 mmol, prepared by using the generalpreparation 1) and K₂CO₃ (10.5 mmol) in 30 ml of DMF was treatedaccording to the general preparation 2 to give compound (IV-28), 0.86 g(74%), M⁺ 381.

Elemental analysis: C₂₂H₂₇N₃O₃.2HCl .1/2H₂O ¹HNMR(DMSO-d₆): δ 3.56(m,8H, piperazine-H), 3.77 (s, 3H, CH₃O), 4.14(s, 2H PhCH₂), 4.35(s, 2H,NCH₂CON), 5.09 (s, 2H, COCH₂N), 7.26-8.03 (m, 9H, ArH).

Example 15 (IV-29)N¹-phenacyl-N⁴-[2-(R-1-phenylethanamino)-2-oxo-ethyl]piperazinedihydrochloride

A mixture of (R)-2-chloro-N-(1-phenylethyl)acetamide (3 mmol),N-phenacyl piperazine dihydrochloride (2.5 mmol) and K₂CO₃ (8.75 mmol)in 30 ml of DMF was treated according to the general preparation 2 togive compound (IV-29), 0.72 g (63.2%), M⁺ 365.

Elemental analysis: C₂₂H₂₇N₃O₂.2HCl.H₂O ¹HNMR (DMSO-d₆): δ 1.44 (d, 3H,NHCHCH₃), 3.55 (m, 8H, piperazine-H), 4.04 (s, 1H, PhCHCH₃), 4.35(s, 2H,NCH₂CON), 5.12 (s, 2H, COCH₂N), 7.23-8.14 (m, 10H, ArH).

Example 16 (IV-30)N¹-phenacyl-N⁴-[2-(4-methoxybenzylamino)-2-oxo-ethyl]piperazinedihydrochloride

A mixture of N-(4-methoxybenzyl)-2-chloroacetamide (3.65 mmol),N-phenacyl piperazine dihydrochloride (3.97 mmol) and K₂CO₃ (10.5 mmol)in 30 ml of DMF was treated according to the general preparation 2 togive compound (IV-30)(61%), M⁺ 381.

Elemental analysis: C₂₂H₂₇N₃O₃ .2HCl.1/2H₂O ¹HNMR(DMSO-d₆):δ3.55(m, 8H,piperazine-H), 3.77(s, 3H, CH₃O), 4.14 (s, 2H PhCH₂N), 4.35(s, 2H,NCH₂CON), 5.12 (s, 2H, COCH₂N), 7.23-8.14 (m, 9H, ArH).

Example 17 (IV-31)N¹-phenacyl-N⁴-[2-(2-pyridylmethylamino)-2-oxo-ethyl]piperazinetrihydrochloride

A mixture of 2-chloro-N-(pyridin-2-ylmethyl)acetamide (1.3 mmol),N-phenacyl piperazine dihydrochloride (1 mmol), and K₂CO₃ (8.75 mmol) in30 ml of DMF was treated according to the general preparation 2 to givecompound (IV-31), 0.7 g (60.45%), M⁺ 381.

Elemental analysis: C₂₀H₂₄N₄O₂.3HCl ¹HNMR (DMSO-d₆): δ3.33-3.54(m, 8H,piperazine-H), 4.33(s, 2H, NHCH₂), 4.39 (s, 2H, NCH₂CON), 5.12(s, 2H,COCH₂N), 7.46-8.96 (m, 9H, ArH, pyridine-H).

Example 18 (IV-32)¹-phenacyl-N⁴-[2-(3,4-methylenedioxyphenylmethylamino)-2-oxo-ethyl]piperazinedihydrochloride

A mixture of N-[1-(3,4-methylenedioxyphenyl)methyl]-2-chloroacetamide (5mmol), N-phenacyl piperazine dihydrochloride (5 mmol) and K₂CO₃ (17.5mmol) in 60 ml of acetone was treated according to the generalpreparation 2 to give compound (IV-32), 0.76 g (63.45%), M⁺ 395.

Elemental analysis: C₂₁H₂₅N₂O₃ .2HCl.1/2H₂O ¹HNMR(DMSO-d₆): δ2.42(s, 2H,OCH₂O), 3.33-3.54(m, 8H, piperazine-H), 4.33(s, 2H, NH CH₂), 4.39(s, 2H,NCH₂CON), 5.12 (s, 2H, COCH₂N), 7.25-8.11 (m, 8H, ArH).

Example 19(IV-33)N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazinedihydrochloride

A mixture of chloroacetylbenzylamine (0.43 g, 2.3 mmol),N-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]piperazine dihydrochloride(0.8 g, 1.9 mmol, prepared by using the general preparation 1) and K₂CO₃(0.95 g, 6.6 mmol) in 40 ml of acetone was treated according to thegeneral preparation 2 to give compound (IV-33), 0.86 g (60%), M⁺ 480.

Elemental analysis (found): C₂₇H₃₀ClN₃.2HCl.H₂O (C, 57.21%; H, 5.89%; N,7.10%). ¹HNMR(DMSO-d₆): δ1.68(s, 3H, CH₃CH), 3.64-4.02(br, 11H,piperazine-H), 4.40(s, 3H, OCH₃), 5.37(t, 2H, PhCH2), 7.24-7.70(m, 10H,ArH), 8.34(m, 1H, NH).

Example 20 (IV-34) N¹-benzoyl-N⁴-(2-phenylethyl-2-ol)piperazinehydrochloride

A mixture of N-benzyl-piperazine dihydrochloride (20 mmol, prepared byusing the general preparation 3, yield 70%), 2-chloro-1-phenylethanone(24 mmol), K₂CO₃ (70 mmol) and KI(2 mmol) in 100 ml of acetone wastreated according to the general preparation 2 to giveN¹-benzyl-N⁴-phenacyl piperazine dihydrochloride (67%).

The above product (3.5 mmol) in 60 ml of methanol was treated accordingto the general preparation 4 to giveN¹-benzyl-N-⁴-(phenylethyl-2-ol)piperazine dihydro-chloride (65%).

N¹-benzyl-N⁴-(phenylethyl-2-ol)piperazine dihydrochloride (2.28 mmol)was treated according to the general preparation 5 to giveN-(phenylethyl-2-ol)piperazine dihydrochloride (1.94 mmol) (85%), whichwas treated with benzoyl chloride (2.33 mmol) and K₂CO₃ (6.8 mmol) in 10ml of DMF according to the general preparation 2 to give compound(IV-34), 0.51 g (76.4%), mp 116-118° C., M⁺ 311.

Elemental analysis (found): C₁₉H₂₂N₂O₂.HCl ¹HNMR (DMSO-d₆): δ3.27-3.65(m, 10H, NCH₂, piperazine-H), 5.21 (m, 1H, CHOH), 7.27-7.47 (m, 10H,ArH). IR (KCl): v3300, 2940, 1625, 1490, 1100 cm⁻¹.

Example 21 (IV-36) N¹-phenacyl-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

A mixture of N-(2-phenylethyl-2-ol) piperazine dihydrochloride (3 mmol,prepared in the similar procedure of example 20),2-bromo-1-phenylethanone (3.6 mmol) and K₂CO₃ (10.5 mmol) in 15 ml ofDMF was treated according to the general preparation 2 to give compound(IV-36), 0.81 g (67.2%), mp 220-221° C., M⁺ 325.

Elemental analysis (found): C₂₀H₂₄N₂O₂ .2HCl.1/2H₂O. IR (KCl): v3300,2970, 1690, 1620, 1590, 1060 cm⁻¹

Example 22 (IV-37)N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(2-phenylethyl-2-ol) piperazinedihydrochloride

A mixture of N-(2-phenylethyl-2-ol) piperazine dihydrochloride (2 mmol),N-benzyl-2-chloroacetamide (2.4 mmol), and K₂CO₃ (7 mmol) in 10 ml ofDMF was treated according to the general preparation 2 to give compound(IV-37), 0.64 g (75.1%), mp 206-208° C., M⁺ 354.

Elemental analysis (found): C₂₁H₂₇N₃O₂.2HCl. IR (KCl): v 3350, 3220,2980, 1680, 1600, 1540 cm⁻¹

Example 23 (IV-38) N¹-(4-methoxyphenacyl)-N⁴-(3-phenylpropyl-3-ol)piperazine dihydrochloride

A mixture of N-benzyl-piperazine dihydrochloride (2 mmol),3-bromo-1-phenylpropan-1-one (36 mmol), K₂CO₃ (105 mmol) and KI (3 mmol)in 150 ml of acetone was treated according to the general preparation 2to give N¹-benzyl-N⁴-(3-oxo-3-phenylpropyl)-piperazine dihydrochloride(22 mmol)(73.2%).

A mixture of the above product (3.5 mmol) in 60 ml of methanol wastreated according to the general preparation 4 to giveN¹-benzyl-N⁴-[(3-hydroxy-3-phenyl)propyl]piperazine dihydrochloride (2.6mmol)(75%), which was treated according to the general preparation 5 togive N-[(3-hydroxy-3-phenyl)propyl]piperazine dihydrochloride (2.07mmol)(83%).

The above product (2 mmol) was treated with2-chloro-1-(4-methoxyphenyl)ethanone (2.4 mmol) and K₂CO₃ (7 mmol) in 10ml of DMF according to the general preparation 2 to give compound(IV-38), 0.62 g (70.4%), mp 240-243° C., M⁺ 368.

Elemental analysis (found): C₂₂H₂₈N₂O₃.2HCl (C, 60.21%; H, 7.03%; N,6.31%).

Example 24 (IV-39)N¹-(4-chlorophenacyl)-N⁴-(2-phenylethyl-2-ol)piperazine dihydrochloride

A mixture of N-(2-phenylethyl-2-ol)piperazine dihydrochloride (2 mmol),2-bromo-1-(4-chlorophenyl)ethanone (2.4 mmol) and K₂CO₃ (7 mmol) in 10ml of DMF was treated according to the general preparation 2 to givecompound (IV-39), 0.63 g (70%), M⁺ 359.

Elemental analysis (found): C₂₀H₂₃ClN₂O₂.2HCl.H₂O. IR (KCl): v3300,2960, 1700, 1620, 1570, 1060 cm⁻¹

Example 25 (IV-40)N¹-(4-methoxyphenacyl)-N⁴-(2-phenylethyl-2-ol)piperazine dihydrochloride

A mixture of N-(2-phenylethyl-2-ol)piperazine dihydrochloride (2 mmol),2-bromo-1-(4-methoxyphenyl)ethanone (2.4 mmol) and K₂CO₃ (7 mmol) in 10ml of DMF was treated according to the general preparation 2 to givecompound (IV-40), 0.66 g (71%), M⁺ 354.

Elemental analysis (found): C₂₁H₂₆N₂O₃.2HCl.2H₂O. IR (KCl): v3300, 2950,1690, 1625, 1550, 1060 cm⁻¹

Example 26 (IV-41) N¹-(1-benzoylethyl)-N⁴-(2-phenylethyl-2-ol)piperazine dihydrochloride

A mixture of N-(2-phenylethyl-2-ol) piperazine dihydrochloride (2 mmol),2-bromo-1-phenylethanone (2.4 mmol) and K₂CO₃ (7 mmol) in 10 ml of DMFwas treated according to the general preparation 2 to give compound(IV-41), 0.52 g (63%), M⁺ 338.

Elemental analysis (found): C₂₁H₂₆N₂O₂.2HCl IR (KCl): v3300, 2870, 1750,1610, 1590, 1030 cm⁻¹

Example 27 Preparation of Tablets

The compound in this invitation  15 mg Starch  55 mg Sugar 190 mgCalcium stearate  4 mg

Example 28 Preparation of an Injection Fluid

The compound in this invitation  3 mg Sodium chloride 10 mg Water 50 mg

Example 29 The Effect of the Compounds for the Maximum Contraction ofthe Ileo Muscles of Cavy Induced by L-Glu

According to the literature (Luzzi, Br J Pharmacol, 95:1271, 1988),maximum contraction of isolated longitudinal ileomuscle preparations ofguinea pig induced by L-Glu, were used to examine the activities of thecompounds on the NMDA receptor.

Methods: L-Glu was used to induce the contraction of the isolated musclepreparations, Ketamine (the antagonist of NMDA receptor ion channel) andIfenprodil (the antagonist of NMDA receptor polyamine site) were used asthe positive control. 13 compounds were tested, the results indicatethat 8 compounds could inhibit from the maximum contraction induced byGlu, showed the antagonistic activities on NMDA receptor (10⁻⁵M); 5compounds (IV-1, 9, 10, 11, 35) could excite preparations directly andinduce preparations contraction, showed Glu-like excited action. Theresults were showed on Table 2.

TABLE 2 Activities of the Compounds on Inhibiting Muscle ContractionCompound antagonism %* Compound excitation IV-2 25 IV-1   3 × 10⁻⁶ IV-337 IV-9 10⁻⁵ IV-5 30 IV-10 10⁻⁵ IV-6 25 IV-11 10⁻⁵ IV-7 25 IV-35   3 ×10⁻⁵ IV-8 25 L-Glu 3.89 × 10⁻⁵ IV-23 40 IV-34 25 Ket 5.61 × 10⁻⁷Ifenprodil 41%(10⁻⁵) *represents the restrain rate of compound (10⁻⁵M)inducing the contraction of preparations

Example 30 Anti-Cerebral Anoxia of the Compounds in Mice

With the mice models of anoxia induced by sodium nitrite (225 mg/kg,ip), the rate of the prolonging the survival duration of the mice wasobserved to evaluate the compound's activities of against anoxia. Of the40 compounds (20 mg/kg sc) in this invention screened, the result showedthat these compounds could prolong to various degrees the survivalduration of the mice. The rates of the prolongation of 9 compounds(IV-2, 10, 23, 32, 34, 36, 39, 40, 41) were more than 50%, whichindicated the effect of anti-cerebral anoxia. IV-23 and IV-2 prolongedthe survival duration by 100% of the animals, showing remarkablyprotective action for cerebral anoxia. (Table 3)

TABLE 3 Anti-cerebral Anoxia Activities of the Compounds ProlongingProlonging Prolonging Prolonging the survival survival survival survivalduration duration duration duration Compound (%) Compound (%) Compound(%) Compound (%) IV-1  3 IV-2  100 IV-3  7 IV-5  22 IV-6  4 IV-7  21IV-8  21 IV-9  30 IV-10 60 IV-11 2 IV-13 32 IV-16 30 IV-17 14 IV-18 25IV-19 18 IV-21 33 IV-22 26 IV-23 100 IV-24 34 IV-25 30 IV-26 36 IV-32 58IV-34 60 IV-35 42 IV-36 65 IV-37 13 IV-39 85 IV-40 60 IV-41 55 IV-44 3IV-48 16 IV-49 30 IV-53 15 IV-54 25 IV-55 4 IV-56 25 IV-58 25 IV-61 22IV-62 36 IV-64 20

Example 31 Protective Activities of the Compounds on Global CerebralIschemia in Rats

The animal models of the bilateral common carotid artery occlusion withexsanguine hypotension in the rats were used to investigate the effectagainst global cerebral ischemia.

Methods: The animals were administrated four compounds (IV-2, 23, 34,36) orally for 3 days before the experiment. One hour afteradministration (20 mg/kg, 5 ml/kg), (saline (5 ml/kg) as vehicle groupand Nimodipine (1 mg/kg) as positive control), the EEG recovery time ofthe rats on reperfusion after 10 min occlusion was observed to evaluatethe effect of compounds on anti-cerebral ischemia. The results of the 4compounds were shown on Table 4.

TABLE 4 Effects of the Compounds on Global Cerebral Ischemia in RatsCompound n Recovery time of EEG (min) Saline 6 22.00 ± 0.89 Nimodipine 613.49 ± 5.55 IV-2 6 16.90 ± 0.86 IV-23 9 13.32 ± 5.10 IV-34 6 14.21 ±2.33 IV-36 6 20.10

The results indicate that compared with the saline group, 3 compounds(IV-23, IV-34 and IV-2) significantly shortened the recovery time of EEGafter cerebral ischemia in rats. These results suggested that thecompounds could protect brain from damage induced byischemia-reperfusion. The activities of IV-23 and IV-34 were comparablewith Nimodipine.

Example 32 Effects of the Compounds on Focal Cerebral Ischemia in Rats

The focal ischemia rat model by occlusion of middle cerebral artery(MCA) was used to determine the protective effects of the compounds onfocal cerebral ischemia. The infarct size after focal cerebral ischemiaand the weight percentage of cerebral hemisphere were calculated toevaluate the compounds' effects on focal cerebral ischemia. The resultsof the two compounds (IV-20, 21, 22, 23, 33) are shown on Table 5.

TABLE 5 Effects of the Compounds (20 mg/kg p.o.) on Focal CerebralIschemia Neurological deficit Right After hemisphere- Percentage of noperation 24 h Weight (g) Infarct volume (g) infarct volume (%) Saline10 9.6 ± 0.5 8.2 ± 1.8  0.74 ± 0.02 0.21 ± 0.08 28.8 ± 10.6 Nimodipine 89.3 ± 1.7 9.0 ± 4.1*  0.730 ± 0.017* 0.188 ± 0.013 25.7 ± 1.7  IV-20 89.5 ± 0.6 8.8 ± 1.3* 0.74 ± 0.01 0.14 ± 0.04 18.80 ± 5.61* IV-21 8 9.8 ±0.5 6.8 ± 2.5* 0.76 ± 0.02 0.12 ± 0.07 15.53 ± 8.27* IV-22 8 9.6 ± 0.97.4 ± 2.4* 0.73 ± 0.01 0.10 ± 0.02  13.61 ± 3.31** IV-23 8 9.4 ± 1.5 4.2 ± 1.3** 0.737 ± 0.029 0.057 ± 0.012  13.3 ± 1.7** IV-33 8 9.6 ± 0.68.4 ± 1.5* 0.75 ± 0.02 0.12 ± 0.04  15.74 ± 5.70** *P > 0.05, **P < 0.01compared with saline group

Percentage of infarct volume: IV-23, IV-33 and IV-22 (20 mg/kg, ig)decreased the infarct region weight and percentage of infarct regionweight to right hemisphere weight significantly (p<0.01); The Nimodipinegroup (20 mg/kg) showed no difference compared with the saline group(p=0.072).

Neurological deficit score: IV-23 decreased the rat Neurological deficitscores significantly, stronger than Nimodipine, 24 hours afteroperation. The results showed that compound IV-23 has a betterprotective effect on focal cerebral ischemia induced by occluded middlecerebral artery than others.

Example 33 Pharmacological Study of Compound IV-23

1. The Preclinical Pharmacodynamic Results of IV-23 in Animals

(1) The Anti-Anoxia Effects of IV-23 in Mice

a. Anoxia Caused by Sodium Nitrite

One model was established to test the time needed for mice to diebecause of anoxia caused by sodium nitrite (225 mg/kg, ip). IV-23 (20mg/kg, sc) can prolong the time for 100%, indicating significantanti-cerebral anoxic anoxia activity.

b. Anoxic Anoxia Experiment

Methods: Male Kunming mice were divided into 8 groups, 12 mice for eachgroup. One group is injected subcutaneously with saline (0.2 mg/10 g,sc), other groups with ACEA1021 (NMDA receptor antagonist under clinicaltrial) or IV-23. 30 minutes after administration, the animals were putseparately into wide-mouth bottles with soda lime, which more quicklyclosed. The survival time for each mice was recorded, and the groupaverage of survival time was calculated and compared with the salinegroup.

Experimental results: The average survival time of the saline group was14.05±0.65 minutes; The survival time of the IV-23 and ACEA-1021 groupswas significantly longer in comparison (Table 6). ED₅₀ for IV-23 andACEA-1021 were 6.2 mg/kg and 29.2 mg/kg, respectively, suggesting aprotective effect of IV-23 for cerebral anoxia.

TABLE 6 Protective Effects of IV-23 on Mice Cerebral Anoxia Averagesurvival time Group Dose (mg/kg, sc.) (min)(means ± S.E.M.) Saline 14.05± 0.65 ACEA-1021 2.5 17.33 ± 1.18* 5 18.20 ± 0.82** 10 19.47 ± 1.17** 2020.04 ± 1.38** IV-23 10 16.46 ± 0.89* 20 17.11 ± 0.53** 40 19.26 ±0.91** 80 20.04 ± 1.56** Note: Compared with saline: *p < 0.05, **p <0.01

(2) Protection of IV-23 Against Global Cerebral Ischemia in Rats

The effect of IV-23 on cerebral ischemia-reperfusion in rats was studiedusing four arteries reversible occlusion by measuring the recoveringtime of the electroencephalogram and the righting reflex (a short timeindicates a strong effect). IV-23 (5 mg/kg, 10 mg/kg, 20 mg/kg, ip,respectively) shortened obviously the recovering time and the rightingreflex time compared with the saline group and the Nimodipine group (1mg/kg, p<0.01), indicating that IV-23 has protection on global cerebralischemia-reperfusion injury in rats.

TABLE 7 The Influence of IV-23 on Global Cerebral Ischemia-reperfusionInjury in Rats Time for Time for electroencephalogramelectroencephalogram to Time for righting reflex Group N to disappear(S)recover (S) to recover (S) Saline 7 345.0 ± 380.5 2737.5 ± 1032.2 1895.0± 986.7 Nimodipine 5 396.0 ± 559.8^(Δ) 3264.0 ± 336.4^(Δ) 1284.0 ±1319.8^(Δ) High-dose 4 566.3 ± 430.3^(*Δ)  70.3 ± 20.1^(***ΔΔΔ)  147.0 ±123.1^(*ΔΔΔ) Middle-dose 7 557.1 ± 639.4^(*Δ)  334.3 ± 674.3^(***ΔΔΔ) 822.8 ± 741.9^(*ΔΔ) Low-dose 6 275.5 ± 338.1^(*Δ)  184.6 ±214.1^(***ΔΔΔ)  550.0 ± 282.5^(*ΔΔΔ) Δ P > 0.05, ΔΔ P < 0.05, ΔΔΔ P <0.01 compared with a saline group *P > 0.05, **P < 0.05, ***P < 0.01compared with a Nimodipine group

(3) Protection of IV-23 on Focal Cerebral Ischemia in Rats.

a. The Focal Cerebral-Infarction of Using Electrical Coagulation toOcclude MCA:

The percentage for necrosis: compared with the vehicle control group, 10mg/kg and 20 mg/kg of IV-23 significantly decreased the infarct size andthe ratio between infarct size and the right cerebral hemisphere(p<0.01). For the 5 mg/kg group, the percentage of the rat's infarctsize was decreased, but the difference is not significant (p=0.098). Theeffect is not significant for the Nimodipine mg/kg. The behavioral scoreof 24 hours after the operation: the score of the middle-dose and thehigh-dose groups were significantly decreased, the difference formiddle-dose group was significantly (p<0.01) better than the group ofNimodipine. The results show that IV-23 has a great theraputic effect onthe focal cerebral-infarction caused by ligation of MCA (Table 8), theeffect is dose-related.

TABLE 8 The Effects of IV-23 on Rat Histology and Behavior Caused byLigation of Cerebral Medium-Sized Artery The neurological The weight ofNumber deficit score the right The percentage of the After the cerebralThe weight of of infarction Group animal operation 24 h hemisphere (g)infarct area (g) (%) Negative 10 9.6 ± 0.5 8.2 ± 1.8  0.74 ± 0.02 0.21 ±0.08 28.8 ± 10.6 criteria Nimodipine 9 9.7 ± 0.5 8.3 ± 2.0* 0.74 ± 0.010.15 ± 0.05 20.5 ± 6.8* High-dose 9 9.7 ± 0.5 6.7 ± 2.6* 0.73 ± 0.020.11 ± 0.05  14.2 ± 6.8*** middle-dose 10 9.6 ± 0.5  5.6 ± 2.7** 0.73 ±0.01 0.10 ± 0.06  13.4 ± 8.4*** Low-dose 10 9.7 ± 0.5 8.1 ± 2.0* 0.73 ±0.01 0.15 ± 0.06 20.8 ± 8.8* *P > 0.05, **P < 0.05, ***P < 0.01 comparedwith negative criteria

a. Focal brain injury caused by photochemical induction of occlusion ofthe artery:

Compared with the vehicle (saline), IV-23 can significantly improve therat's neurological deficit (p<0.05), decrease the weight of infarctarea, the percent by weight of infarct area, per the right cerebrahemisphere (p<0.01). The percentage of infarction was lowered by 52% at24 hours after operation. Compared with ACEA-1021, IV-23 cansignificantly reduce the neurological deficit score and the percentageof infarct area (p<0.01) (See Table 9).

TABLE 9 The Effect Of IV-23 on the Histology and Neurological DeficitDue to Occlusion of MCA Induced by Photochemical Reaction Weight ofScore of praxiology right Weight of Dose After hemisphere necrotic areaNecrotic Group (mg/kg) Number operation 24 h (g) (g) percent (%)Negative 0 8 9.4 ± 0.5 9.1 ± 0.8  0.68 ± 0.01 0.16 ± 0.01   23 ± 1  Positive 2 8 9.5 ± 0.5 7.1 ± 1.9** 0.70 ± 0.01 0.12 ± 0.02*** 17 ± 2***IV-23 2 7 9.6 ± 0.5  5.4 ± 1.9***^(Δ) 0.68 ± 0.01   0.08 ± 0.02***^(ΔΔΔ)  11 ± 3***^(ΔΔΔ) *P > 0.05, **P < 0.05, ***P < 0.01 compared withvehicle. ^(Δ)P > 0.05, ^(ΔΔ)P < 0.05, ^(ΔΔΔ)P < 0.01 compared withpositive control.

b. Temporary occlusion of the right MCA in rats caused by suture. Theresults show that ACEA-1021 can significantly reduce the ratio of volumeafter being under ischemia for 6 hours. Different doses of IV-23 canreduce the percent of volume of infarction significantly, and it isrelated with time of ischemia (Table 10). After 6 hours of ischemia, 5mg/kg will significantly reduce the volume of the cerebral infarction;after 3 hours of ischemia, 5 mg/kg can reduce the volume by 46.3% (Table11).

TABLE 10 Effects on Cerebral Ischemia (N = 10) Dose Percent of infarctGroup (mg/kg) Time of occlusine (hr) (%) (Means ± SEM) P Value Saline 13.76 ± 1.13 Saline 3 15.87 ± 2.28  Saline 6 20.00 ± 0.82  IV-23 5 1 1.31± 0.50 ^(a)>0.05 IV-23 5 3 8.57 ± 1.42 ^(b)<0.05 IV-23 5 6 12.90 ± 1.11 ^(c)<0.001 ^(a)compared with saline for 1 hr ^(b)compared with salinefor 3 hr ^(c)compared with saline for 6 hr

TABLE 11 Effects of Different Doses of IV-23 on Cerebral Ischemia Lengthof Percent of volume Group Dose (mg/kg) ischemia (hr) (Means ± SEM) P

* Saline 6 20.00 ± 0.82 IV-23 2.5 6 15.42 ± 1.71 <0.05 IV-23 5 6 12.90 ±1.11 <0.001 IV-23 10 6 14.92 ± 1.40 <0.01 ACEA-1021 10 6 12.73 ± 1.24<0.001

The three models of focal cerebral ischemia showed that IV-23 reducesthe volume of cerebral ischemic significantly, it has clear protectiveand therapeutic effects, and the effect is much better than that ofNimodipine and ACEA-1021.

Example 34 Mechanism of IV-23 Effects on Cerebral Ischemia

1. Effects on the Hippocampal Neuron of Newborn Rats:

Electro-physiological Analysis: When tested using the whole-cell patchclamp technique with rapidly isolated rat CA1 pyramidal neuron, IV-23inhibited the electric current induced by NMDA (100 μm), and theinhibitive effect showed dose dependency. IC₅₀: 562.7±1.1 μm(n=4, Hillcoefficient 1.17), demonstrating that IV-23 inhibits the depolarizationof the neuronal cell induced by NMDA, confirming that IV-23 is anantagonist of the NMDA receptor (See FIG. 1).

Methods: The whole-cell patch-clamp technique. Separate the rat'shippocampi, slash the brain piece into 500 μm thick. Get the CA1 area ofhippocampi, put it into artificial cerebral spinal fluid (ACSF) toincubate for more than 1 hour. Then the solution is oxygen saturated.After the incubation of the brain piece, put it into ACSF with proteaseXIII (1 mg/ml) for 5 minutes. Using trypsin inhibitor type II-S (3mg/ml) to terminate the protease digestion, and then using test tube tobreak the brain piece to obtain free cells, let it stand for a while andthen start the experiment.

The electro-physiological experiment used the technique of whole-cellpatch-clamp. The amplifier in the experiment is Axon-200A patch-clampamplifier, with the DigiData-1200A as a sampling port. The software usedis AxoScope Version 1.0. The experiment uses as a standard the electriccurrent generated by the whole-cell. The effect of various samples onthe electric current was observed. IC₅₀ was determined by proportion ofdifferent concentrations to the electric current of NMDA.

Results: IV-23 inhibits the electric current induced by NMDA in aconcentration dependant way. IC₅₀ is 562.7±1.1 μm(n=4), the HillCoefficient is 1.17, indicating IV-23's inhibition to the depolarizationof the neuronal cells.

2. IV-23 Reduces Injury to Neuronal Cells Caused By NMDA:

Primary culture of rat cerebral cortical neuronal cells were used. Theresults showed that IV-23 significantly reduced the increase of LDHspecific activity caused by NMDA in the supernatant of primary cultureof neuronal cell (Table 12), indicating that IV-23 has a protectiveeffect on the injury (Table 13). This is further evidence that IV-23 isa new NMDA receptor antagonist, and has anti-cerebral ischemic injuryfunctions as well.

TABLE 12 Effect of NMDA on Neurons (n = 12) LDH activities (U/g protein)Concentration (mmol/L) (mean ± SEM) Normal 0.68 ± 0.05 0.1 1.51 ± 0.25**0.5 1.63 ± 0.19** NMDA 1 1.74 ± 0.17** 2 2.38 ± 0.31** **P < 0.01,compared with normal

TABLE 13 Protective Effect of IV-23 on Neurons Damaged With NMDA (1mmol/L) (N = 12) Concentration LDH activities (mean ± Protective rate(mol/L) (U/g protein) SEM) (%) Normal 1.74 ± 0.17 saline IV-23 10 1.86 ±0.20 0 50  1.23 ± 0.14* 48.1 100  1.05 ± 0.16** 65.1 200  0.79 ± 0.19**89.6 *P < 0.05, **P < 0.01, compared with normal saline group.

Example 35

3. Acute Toxicity of IV-23

LD₅₀ (mice, mg/kg, 95% confidence limit) of i.v. and p.o. are132.77(115.79-147.86) mg/kg and 855.73(737.87-970.70) mg/kg,respectively.

4. The Genotoxicity of IV-23

The Ames test of IV-23 was negative.

The rodent microkernel experiment of IV-23 was negative.

The chromosome aberration trial in mammalian cultural cell was negative.

5. The Antiplatelet Agglutination of IV-23

At a concentration of 1×10⁻⁴M, IV-23 did inhibit rats plateletaggregation induced by ADP, which suggested that its anti-cerebralinfarction activities are not by the way of anticoagulation.

6. Conclusions:

IV-23 is a novel antagonist of NMDA receptor. It has an obvious effecton protecting the rats' primary culture nerve cell from the damageinduced by NMDA. For focal cerebral infarction induced by rats' cerebralarterial ligation, oral administration (10 mg/kg) and injection (2.5mg/kg) have evident therapeutic effects. IV-23's therapeutic action isbetter than Nimodipine and positive control ACEC-1021. IV-23 has aprotective action against the global cerebral ischemia reperfusiondamage. The induced mutation experiment is negative. IV-23 has shownobvious activity and safety on the models of rats' global and focalcerebral ischemia, indicating that it has preventive and therapeuticapplications for human cerebral infraction.

1. A compound of Formula I:

wherein Ar₁ and Ar₂ independently represent:

each of R₁, R₂, R₃ and R₄ represents hydrogen, a C₁-C₃ alkyl group, a C₅or C₆ cycloalkyl group, phenyl, substituted phenyl, hydroxyl, methoxyl,ethoxyl, amino, substituted amino, halogen, carboxylic acid, carboxylicester, nitryl, or acetonitrile group, X represents —CHOH—, —CO—, —CONH—,—CH═CH—, O, N, —SO₂— or —SO—, Y represents C, N, or O, Z represents afive or six-membered ring containing at least one of C, S, N or O, andn, m₁ and m₂ independent of one another represent 0, 1, 2, 3; in theform of a racemate, enantiomer, diastereomer, a mixture of theenantiomers or diastereomers thereof, physiologically compatible acidicand basic salt, a salt with a cation or a base or with anions and/oracids or in the form of a free acid or base.
 2. The compound of claim 1,wherein the salt is selected from the group consisting of hydrochloride,hydrobromide, sulfate, trifluoroacetate and methansulfonate.
 3. Thecompound according to claim 2, wherein the salt is hydrochloride orhydrobromide.
 4. The compound according to claim 1, wherein the saltcontains about 0.5-3 molecules of hydrate water.
 5. The compoundaccording to claim 1, wherein each of R₁, R₂ and R₃ represents any oneof hydrogen, a C₁-C₃ alkyl, hydroxyl, amino, substituted amino orcarboxylic ester group; R₄ represents hydrogen, hydroxyl, alkoxy,nitryl, halogen, amino, substituted amino or a C₁-C₃ alkyl group.
 6. Thecompound according to claim 1, wherein X represents —CHOH—, —CO— or—CONH—.
 7. The compound according to claim 1, wherein Y represents C orN.
 8. The compound according to claim 1, wherein the compound isselected from the group consisting of: IV-1N¹-benzoyl-N⁴-phenacyl-piperazine, IV-2 N¹,N⁴-diphenacyl-piperazine,IV-3 N¹-(4-nitrobenzoyl)-N⁴-phenacyl-piperazine, IV-4N¹-(2-acetoxy-1-oxo-2-phenylethyl)-N⁴-(1- benzoylethyl) piperazine, IV-5N¹-phenacyl-N⁴-(4-chlorophenacyl) piperazine, IV-6 N¹,N⁴-di(4-chlorophenacyl) piperazine, IV-7N¹-(2-naphthoylmethyl)-N⁴-phenacyl-piperazine, IV-8N¹-(1-benzoylethyl)-N⁴-phenacyl-piperazine, IV-9N¹-phenacyl-N⁴-(4-methoxyphenacyl) piperazine, IV-10 N¹,N⁴-di(1-benzoylethyl) piperazine, IV-11 N¹-phenacyl-N⁴-(4-nitrophenacyl)piperazine, IV-12 N¹-phenylacetyl-N⁴-phenacyl-piperazine, IV-13N¹-(1-benzoylethyl)-N⁴-phenacyl-piperazine, IV-14 N¹,N⁴-di(4-methoxyphenacyl) piperazine, IV-15 N¹-phenacyl-N⁴-[(2-hydroxy)phenylacetyl] piperazine, IV-16 N¹-(4-methoxyphenacyl)-N⁴-[(2-hydroxy)phenylacetyl] piperazine, IV-17 N¹-(1-benzoylethyl)-N⁴-[2-hydroxy-2-(4-chlorophenyl)acetyl] piperazine, IV-18N¹-(1-benzoylethyl)-N⁴-[(2-hydroxy) phenylacetyl] piperazine, IV-19N¹-phenacyl-N⁴-[2-hydroxy-2-(4-chlorophenyl) acetyl] piperazine, IV-20N¹-phenacyl-N⁴-[1-(5-chloro-6-methoxy-2-naphthoyl) ethyl]piperazine,IV-21 N1-[2-(benzylamino)-2-oxo-ethyl]-N⁴-cinnamyl piperazine, IV-22N¹-phenacyl-N⁴-(2,4-difluorobenzylsulfonyl) piperazine, IV-23N¹-phenacyl-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine, IV-24N¹-phenacyl-N⁴-[2-(phenylamino)-2-oxo-ethyl] piperazine, IV-25N¹,N⁴-di[2-(benzylamino)-2-oxo-ethyl] piperazine, IV-26N¹-(1-benzoylethyl)-N⁴-[2-(benzylamino)-2-oxo- ethyl] piperazine, IV-27N¹-(4-chlorophenacyl)-N⁴-[2-(benzylamino)-2-oxo- ethyl] piperazine,IV-28 N¹-(4-methoxyphenacyl)-N⁴-[2-(benzylamino)-2-oxo- ethyl]piperazine, IV-29 N¹-phenacyl-N⁴-[2-(R-1-phenylethanamino)-2-oxo- ethyl]piperazine, IV-30 N¹-phenacyl-N⁴-[2-(4-methoxybenzylamino)-2-oxo- ethyl]piperazine, IV-31 N¹-phenacyl-N⁴-[2-(2-pyridylmethylamino)-2-oxo- ethyl]piperazine, IV-32 N¹-phenacyl-N⁴-[2-(3,4-methylenedioxybenzylamino)-2-oxo-ethyl] piperazine, IV-33N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine, IV-34N¹-benzoyl-N⁴-(2-phenylethyl-2-ol) piperazine, IV-35N¹-(4-nitrobenzoyl)-N⁴-(2-phenylethyl-2-ol) piperazine, IV-36N¹-phenacyl-N⁴-(2-phenylethyl-2-ol) piperazine, IV-37N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(2- phenylethyl-2-ol) piperazine,IV-38 N¹-(4-methoxyphenacyl)-N⁴-(3-phenylpropyl-3-ol) piperazine, IV-39N¹-(4-chlorophenacyl)-N⁴-(2-phenylethyl-2-ol) piperazine, IV-40N¹-(4-methoxyphenacyl)-N⁴-(2-phenylethyl-2-ol) piperazine, IV-41N¹-(1-benzoylethyl)-N⁴-(2-phenylethyl-2-ol) piperazine, IV-42N¹-[2-(4-acetamidophenyl)-2-oxo-ethyl]-N⁴-(2- phenylethyl-2-ol)piperazine, IV-43 N¹-(2-hydroxy-1-oxo-2-phenylethyl)-N⁴-(phenylpropane-2-yl-3-ol) piperazine, IV-44N¹-(S-2-hydroxy-1-oxo-2-phenylethyl)-N⁴-(1- benzoylethyl) piperazine,IV-45 N¹-phenacyl-N⁴-(3-fluorophenylmethylsulfonyl) piperazine, IV-46N¹-phenacyl-N⁴-(3-bromophenylmethylsulfonyl) piperazine, IV-47N¹-phenacyl-N⁴-(3-iodophenylmethylsulfonyl) piperazine, IV-48N¹-phenacyl-N⁴-(3-cyanophenylmethylsulfonyl) piperazine, IV-49N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-[2-(1-phenylethanamino)-2-oxo-ethyl] piperazine, IV-50N¹-phenacyl-N⁴-(2-fluorobenzylsulfonyl) piperazine, IV-51N¹-phenacyl-N⁴-(2,5-difluorobenzylsufonyl) piperazine, IV-52N¹-phenacyl-N⁴-(2,5-dichlorobenzylsufonyl) piperazine, IV-53N¹-phenacyl-N⁴-(4-phenoxybenzylsulfonyl) piperazine, IV-54N¹-phenacyl-N⁴-[2- (benzenesulfonylmethyl)benzylsulfonyl] piperazine,IV-55 N¹-phenacyl-N⁴-(4-trifluoromethylbenzylsulfonyl) piperazine, IV-56N¹-phenacyl-N⁴-(4-phenylbenzylsulfonyl) piperazine, IV-57N¹-phenacyl-N⁴-(3-methoxybenzylsulfonyl) piperazine, IV-58N¹-phenacyl-N⁴-[4-(2-cyanophenyl)benzylsulfonyl] piperazine, IV-59N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(2,4- difluorobenzylsulfonyl)piperazine, IV-60 N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(2,5-difluorophenylmethylsulfonyl) piperazine, IV-61N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-[4-(2- cyanophenyl)benzylsulfonyl]piperazine, IV-62 N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-[2-(benzenesulfonylmethyl)benzyl sulfonyl] piperazine, IV-63N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(3,4- dichlorobenzylsulfonyl)piperazine, IV-64 N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-(4-nitrobenzylsulfonyl) piperazine, IV-65N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-[2-(benzylamino)-2-oxo-ethyl] piperazine, IV-66N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-(4- methoxyphenacyl)piperazine, IV-67 N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-(4-chlorophenacyl) piperazine, IV-68N¹-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl]-N⁴-(4-methylsulfonylphenacyl) piperazine, IV-69N¹-[2-(benzylamino)-2-oxo-ethyl]-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine, and IV-70N¹-(4-chlorophenacyl)-N⁴-[1-(5-chloro-6-methoxyl-naphthalen-2-yl)-propane-2-yl-1-ol] piperazine.


9. The compound according to claim 8, wherein the compound isN¹-phenacyl-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazine.
 10. Apharmaceutical composition comprising a compound according to claim 8,and a pharmaceutically acceptable excipient.
 11. The pharmaceuticalcomposition according to claim 10, wherein the compound isN¹-phenacyl-N⁴-[2-(benzylamino)-2-oxo-ethyl]piperazine, which is in theform of a racemate, enantiomer, diastereomer, a mixture of theenantiomers or diastereomers thereof, physiologically compatible acidicand basic salt, a salt with a cation or a base or with anions and/oracids or in the form of a free acid or base.
 12. A method for treatingischemic cerebral apoplexy, the method comprising administering to apatient in need thereof a pharmaceutical composition of claim
 10. 13. Aprocess for preparing a compound according to claim 1, wherein theprocess follows the following synthetic route:

wherein: X=—CHOH—, —CO—, —CONH or —SO₂—, and m₁, m₂, or n is 0, 1, 2, or3; and wherein the reaction medium for steps a, b, c and d comprises thefollowing components:


14. A process for preparing a compound according to claim 1, wherein theprocess follows the following synthetic route:

wherein X=CHOH wherein m₁, m₂, or n is 0, 1, or 3 and wherein thereaction medium for steps e, f, g, h and b comprises the followingcomponents: